Thiolurethanes and processes for



Patented June. 16, 1953 THIOLURETHANES AND PROCESSES FOR PREPARING THEM John Weijlard, Maplewood, and Max Tishler, Westfield, N. J., assignors to Merck & 00., Inc., Rahway, N. J., a corporation of'New Jersey No Drawing. Original application December 13, I 1949, Serial No. 132,793. Divided and this application June 25, 1952, Serial No. 295,113

This invention is concerned generally with a new group of antispasmodlcs related to choline. More particularly, it relates to dimethyl-alkylfl (carbamylmercapto)ethyl ammonium salts wherein both of the hydrogens attached to the nitrogen atom of the carbamyl grouping are replaced by saturated hydrocarbon radicals; to the process for preparing these novel quaternary ammonium salts and to the intermediate products thus obtained.

This application is a division of our eo-pending application Serial No. 132,793, filed December 13, 1949.

Compounds, analogous to the quaternary ammonium salts herein described but wherein oxygen is substituted for sulfur, such as dibutoline sulfate (dimethylethyl B-hydroxyethyl-ammonium sulfate dibutylurethane), have previously been found to be effective antispasmodics. The presently disclosed quaternary salts are, however, greatly superior in antispasmodic effectiveness to said oxygen analogs, and are at the same time much less toxic. Moreover, these novel quaternary salts have been found 'to be far superior to any other known antispasmodics, such as papaverine, Pavatrine and Syntropan. These new salts 8 Claims. (Cl. 260-455) have also been found to have antitubercular activity.

These novel quaternary dimethyl-alkyl-fi-(N, N-disubstituted carbamylmercapto)ethyl ammonium salts may be chemically represented as follows:

. 2 p 7 wherein R and X have fined.

We have discovered that these dimethyl-alkyl- ,8-(N,N disubstituted carbamylmercapto) ethyl ammonium salts, wherein the 'substituents attached to the nitrogen atom of the carbamyl grouping are saturated hydrocarbon radicals,'can be prepared by reacting dimethyl-aminoethylthiol with an N,N-disubstituted carbamyl chloride of the formula:

NOOO1 Rf wherein R1 and R2 are saturated hydrocarbon radicals, for example, a dialkyl carbamyl chloride such as dibutyl carbamyl chloride, diamyl carbamyl chloride, and the like, or a dicycloalkyl carbamyl chloride, such as dicyclohexyl carbamyl chloride, to produce a thiolurethane 0f the formula:

wherein R is an alkyl radicaLRi and R2 are saturated hydrocarbon radical's and X isan anion.

The dimethyl aminoethylthiol starting material .can be prepared by reacting dimethylaminoethyl chloride and sodium hydrosulfide as described in Example 1 hereinbelow. The dialkyl or dicycloalkyl carbamyl chloride can be prepared by reacting the appropriate secondary amine with phosgene according to the procedure set forthin the illustrative examples and de-.- scribed in J. Chem. Soc. 1947, 313. The dimethyl aminoethylthiol and the disubstituted carbamyl chloride, can be prepared in purified form, if desired, by fractional distillation in vacuo.

The reaction between the dimethyl aminoethylthiol and the carbamyl chloride having two saturated hydrocarbon substituents. attached to the nitrogen atom of the carbamyl grouping, for

the significance above de-" example a dialkyl carbamyl chloride such as dibutyl carbamyl chloride, diamyl carbamyl chloride, and the like, or a dicycloalkyl carbamyl chloride such as dicyclohexyl carbamyl chloride, and the like, is ordinarly conducted in the presence of a hydrogen chloride acceptor. The hydrogen chloride acceptor is preferably an organic base such as a compound containing a pyridine ring, such as pyridine, quinoline, picoline, and the like, and preferably an acceptor that also acts as a solvent for the reactants. The reaction is conveniently carried out by heating the reactants under reflux in the presence of pyri' dine under which conditions the reaction is ordinarily complete in approximately 3 hours. The thiolurethane thus produced is conveniently freed of non-basic impurities by evaporating the pyridine, dissolving the residual material in Wa ter, acidifying the aqueous solution and extracting the acidified solution with a water-immiscible organic solvent such as ether to remove impurities. The aqueous solution is then made alkaline and extracted with a Water-immiscible solvent such as chloroform. Upon evaporation of the dried chloroform extracts there is obtained the desired thiolurethane of the formula:

R, on,

Ng-SCH2CH2N R; CH

wherein R1 and Rzare saturated hydrocarbon radicals.

This thiolurethane is then reacted with an alkyl ester of an inorganic acid as, for example,

a dialkyl sulfate, such as diethyl sulfate, an alkyl iodide, such as ethyl iodide, n-propyl-iodide, n.- butyl iodide, n-amyl iodide and the like, toproduce the corresponding quaternary ammonium salt of the formula:

wherein R, R1, R2 and X have the significance defined hereinabove.

The reaction between the thiolurethane and the dialkyl sulfate (preferably diethyl sulfate) is convenientlyconducted by bringing the re actants together in diethyl ether solution at sub-- stantially room'temperature. Under these conditions the reaction is ordinarily substantially complete in about 15 hours and the quaternary dimethylalkyl-B-(N,N-disubstituted carbamyl mercapto ethyl-ammonium ethyl sulfate Which precipitates can be recovered by filtration.

When the thiolurethane is reacted with an alkyl iodide, the. reaction. is, ordinarily carriedjout by mixing the reactants. in the absence of a solvent and agitating the resulting mixture at. a-

The. mixture is ordinarily'al-e wherein R is an alkyl radical, R1 and R2 are saturated hydrocarbon radicals and X is an anion, are the following:

(1) Dimethyl-ethyl-fi-(N,N dicyclohexyl car- 1 bamylmercapto) ethyl-ammonium ethyl sulfate, also named dimethylethyl-B-thiolethyl ammonium ethyl sulfate dicyclohexylurethane; I Dimethyl-mpropyl-fi-(NN dicyclohexylcarbarnylmercapto) ethyl ammonium sulfate, also named dimethyl n propyl p thiolethyl ammonium sulfate dicyclohexylurethane; Dimethyl-n-butyl-p (N,N dicyclohexyl oarbamylmercapto) ethyl ammonium sulfate, also named dimethyl-n-butyl p thiolethyl ammonium sulfate dicyclohexylurethane; 1 l Dimethyl-n-amyl-fi (N,N dicyclohexyl carbamylmercapto) ethyl ammonium sulfate, also named dimethyl-n-amylfi-thiolethyl ammonium sulfate dicyclohexylurethane; Dimethyl-ethyl-s-(N,N-diamyl carbamylmercapto)ethylammonium sulfate, also named dimethylethyl s thiolethyl ammonium sulfate diamylurethane; ,Dimethyl-ethyl-fl- (N,N-diamyl carbamyl' mercapto)ethylammonium ethyl sulfate, also named dimethylethyl-p-thiolethyl ammonium ethyl sulfate diamylurethane; Dimethyl-ethyl-fl-(NN dicyclohexyl-carbamylmercapto ethyl ammonium sulfate, also named dimethylethyl fi-thiolethyl ammonium sulfate dicyclohexylurethane; Dimethyl-ethyl-p '(N,N-dibutyl-carbamylmercapto) ethyl ammonium named dimethylethyl-fi-thiolethyl ammonium iodide dibutylurethane;

named olimethylethyl-fi-thiolethyl ammonium sulfatedibutylurethane; Dimethyl-ethyle-(N,N-dicyclohexyl carbamylmercapto ethyl 7 ammonium iodide. also named dimethylethyl 18* thiolurethyl ammonium iodide dicyclohexylurethane;

Dimethylrn-propyl-B-(N,N dicyclohexyl carbamylmercapto);ethyl ammonium iodide, also named dimethyl n propyl 3' thiolethyl ammonium iodide dicyclohexyl urethane;

Dimethyl-ethyl-s (I-I',N-diamyl-carbamylmercapto ethyl ammonium iodide, also named dimethylethyl-[i-thiolethyl ammonium iodide diamylurethane.

Of particular interest are the first seven quaternary salts listed on the preceding page which have been found to possess outstanding antispasmodic activity.

These compounds were testedv in comparison with Dibutoline sulfate (dimethylethyl-B-hydroxyethyl ammonium sulfate dibutylurethane) on isolated organs for antispasmodic activity as iodide, also Dimethyl-ethyl-B- (N,N-dibutyl carbamyl mercapto ethyl ammonium sulfate, also follows: rabbit intestinef for inhibition of spontaneous activity; guinea pig uterus,- for inhibition of spontaneousv activity; guinea pig intestine, for inhibition of contraction produced by spasmogenic agents, urecholine, acetyl choline,

and in some instances barium chloride.

The results obtained aresummarized in the a following. tablez;

- Inhibition oi Contrac- Inhibition of Spontaneous tions of G. P. Intestine Activity Produced by Spasmogenic 5 Agents Compound I Urecholine Rabbit G. P. Barium Intestine Uterus 6mg; Chloride 1 a 1 -i-ri-+ +++-F" 5 H. .I 6 7 (Dithioline Sulfate). Dibutoline Sulfate 0 As evident from the above table the novel quaternary salts described in this application, and especially the dimethylalkyl-fi-thi'o1ethyl ammonium (ethyl) -'sulfate dicyclohexyl '-urethanes, are'more effective antispasmodics than Dibutoline. Of particular interest is the quarternary salt, dimethylethyl-,8-thiolethyl-ammonium sulfate di-cyclohexyl' urethane (compound 7) which has'been found to be two to three times as potent as Dibutoline in inhibiting the efiect of spasmogenic agents on isolated guinea pig intestine.

choline, histamine, pitocum, or ergotami'ne tartrate.

Compound 7 has been administered orally, subcutaneously, and intravenously to the dog with exteriorized intestinal loop. Good intestinal antispasmodic effects have been observed after administration by all three routes, though on some occasions oral administration 'failed'. When Pavatrine was administtered orally for comparison in two experiments, it succeeded'once and failed once. When Dibutoline iodide has been administered orally in comparable doses (up to 10 mg./kg.), no eiTect has been observed in five trials. In a single experiment, compound 7 (2 mg./kg. subcutaneously), relaxed the uterus of an intact anesthetized guinea pig.

Compound 7 produces mydriasis similar to that observed with Dibutoline when applied topically to the cats' eye, in 5% or 1% solution. Mydriasis was not produced by administration of oral doses up to 2 mg./kg.

The acute toxicity of compound 7 was tested and found to be approximately one-half as toxic as Dibutoline in mice treated with single doses subcutaneously. Determination of LDso (the dosage that will .kill one-half of the animals treated) of the two drugs simultaneously on two different strains of mice gave a figure of about group was given the samedosage of Dibutoline, and a third group served as uninjectedcontrols. At the end of three months, the growth rate of all groups was identical and there was no evidence of toxicity. Examination of the rats after administration for three .months showed nojdivergence from normal in hemoglobin, red cell count, and whitecellcount (total and difierential). No gross morphological changes were found at autopsy,, ex-ce pt for amoderate degree of local tissue irritation at the site of injection (rats are particularly susceptible to local irritation). No local irritation was observed in dogs receiving repeated injections. i s

The antitubercular utility of the new quaternary salts is illustrated by the activities observed 40 when compounds '1 and 9 were tested for in vitro activity against a human type strain of M. tuberculosis designated as H37Rv. These compounds Were-active at 10 micrograms per milliliter.

The following examples illustrate methods of 5 carrying out the presentinvention, but it is to be understood that these examples are given for purposes. of illustration and not of limitation.

Example 1 s 900 gms. (6.25,,moles). of dimethylaminoethylchloridehydrochloride was dissolved in 850 .ml. of water, and 850 ml. of,30% aqueous sodium hydroxide solution, was added. The resulting solution was extracted successively with 1000 m1., 500 ml., and 500, ml. portions of diethyl ether. The extracts were combined and theetherwas evaporated under reduced pressure to produce approximately 700 gms. of crude dimethylaminoethylchloride. V i

2700. gms. (11.2 moles) .ofsodium sulfide nonohydrate wasmelted in a five-literflask provided with a mechanical stirrer, reflux condenser, thermometer and gas inlet tube. Hydrogen sulfide was passed into the molten mixture over a period of 6 to 7 hours, during which time the mixture was stirred rapidly and maintained at atemperature between about 50 and C. The' dimethylamino-ethylchloride'(700 gms.) was added dropwise to the reaction mixture over a period of approximately 2 hours during which time the 'contentsof" the flask were stirred rapidly and maintained at a temperature of 50-60 C. The resulting mixture'was then heated to 90-105 (3., heated underreflux'for 1' hour and "cooled.'- The 75 reaction mixture was extracted successivelywith m g./kg. on Saturdays and Sundays A similar i-tilled; ,1;(temper ature-inadistilling flask 140-190 C.) was collected-to produce l99-gms. of. crude-dimethyl- =amin t ylthioldibutylurethane;- matelyi97.%of.:theory.

i 600m 3.011 ml.-,u,and 3.00:ml.':pQrt Qns ,otdie y ether, the extracts were combined: andxdried over anhydrous calcium sulfate:(Drieritel ,;The ether 1; was-then evaporated from the dry ether solution,

and the residual -material was fractionally dis- ;Tl'1e,traction-distilling at 120-140 C.

aminoethylthiol (yield approximately of theory).

850 gms. of crude dimethylaminoethylthiol (from several preparations) was distilled in vacuo using a 6-8 inch Vigreux column to produce 748 gms. of substantially pure dimethylaminoethylthiol; B. P. 37-43 C./20 mm.; recovery yield apfor proximately 88%. Analysis.-Calcd C4H11NS; C, 45.66; H, 10.54; N, 13.32. Found: C, 45.44; H, 10.56; N, 13.06.

Example 2 1800 ml. of xylene were placed in a flve-liter, j three-necked flask provided with a mechanical stirrer and thermometer. Thepxylene was cooled .to 10.-C. and 297 gms. ,(3 .moles of phosgene was added. A solution containing 516 ,gms. (4 moles) oin-dibutylamine dissolved in 1030 ml. of xylene was addedto the phosgene solution over v aperiod of approximately 5, hours, saidaddition being carried outwhile rapidly stirring the flask contents and maintaining the reaction tempera- ,ture at approximately 5-10 C. The reaction mix- .ture was stirred at room temperature for an additional periodof about 18 hours, the,..dibutylamine hydrochloride which precipitated was removed by. filtration and. theprecipitatdwas washed with seven. 100 ml. portions of xylene.

, The filtrate and washings were combined and the xylene evaporated therefrom by distillation in vacuo. The residue material wasfractionally distilled-using a 12inch Vigreux column to produce approximately 361 g. of substantially pure dibutyl carbamylchloride; B. P. 89-90" -C./2- mm., yield; approximately 94.2% of theory. 7

,Example 3 gms. (0.33 mole) of pure dimethylaminoethylthiol (B. P. 37-43C./20 mm.), prepared as described in Example 1, wasdissolved in 2 ml. of pyridine contained in a one-liter, three- 1 necked flask equipped with a mechanical stirrer and reflux condenser.

,. .dibutylcarbamylchloride, prepared as described in i 57.5 g. (0.0 mole) of n- Example 2, was added to the flask contents. The

resulting, mixturewas ,heatedunder reflux for .approximately,.3 hours. and Was then, e'vaporated to dryness in vacuo. Thev residual material was dissolved in 200 ml. of water andthe pH was producing approximately 76 gms.-,of dimethylyield approxii Eramp le 4 75 :gms; (0.29 mole) of dimethylaminoethylthioldibutylurethane;-"prepared as described in Example 3, was-mixed with 235' g." (1.5moles) of ethyl iodide. The mixture was stirr'ed'until solution was effected and the resulting solution was maintained at 25-30 C. for approximately 3 hours. 750 ml. of diethyl ether-was then added and the mixture was allowed to stand'overnight. The supernatant liquid was decanted, the reaction 1 product wassfilteredand repeatedly washed by decantation with ether and then dried in vacuo toproduce" 116' gms. of; dimethylethyl-fl-thiolethylammonium iodide dibutylurethane; M. P. 56

(3.; yield aproximately 96.6% of theory.

Ewample 5 116 gms.f"(0. 278I-mole) of dimethylethylee-thiolethylammonium iodide dibutylurethane, prepared as described in Example 4,.wasdissolved in 1100 ml. of 90% aqueous ethanol, and v.60 ,gms.j 1(0.19

mole) of powdered silver sulfate was added' to the -solution. a The resulting mixture was stirred rapidly for 2hours, the silver iodidewas removed by filtration and washed with three :50 ml: portions of ethanol: The combined 'filtrate: and

washings were evaporated in vacuo to a syrup. The syrup was dissloved in 400 ml.: of water, the

solution was extracted-with two 200 mL- portions of diethyl ether, and the extracts .were'discarded. The pI-Iof the aqueous solution'was adjusted to 6.7 by the addition of aqueous barium'hydroxide was filtered;

solution, hydrogen 'sulfidewas passed into the solution to precipitateresidual'silver 5 gm. of activated charcoal was added, and the mixture The filtrate'was' avaporated in vacuo to a syrup'and'the residual material was subjected to benzene distillationusing three 150 ml. portions of-benzene. The residual material -was dried over sulfuric acid at a pressure'of 1 mm. to produce 83.8 gms. of dimethylethyl-p- .thiolethyl ammonium sulfate dibutylurethane;

I yield approximately 89.3% of theory. Analysis?- Calcd for CauHesOsN4SaI-I2O; C; 51.-99; I-I;9.89; N,

' 8.08. Found: C; 51.78; H, 10.09;N. 7.80.

.. Example 6 Dicyclohexylamine was reacted with .phosgene according to the procedure described for reacting phosgene with n-dibutylaminein Example 2. After evaporation of the xylene solvent; the

l; residual "material was dissolved in petroleum ether, and the crystalline material which separated ;from-the petroleum ether solutionwas re- ;covered and dried -to produce substantially pure -dicyclohexylcarbamylchloride; M. P. 8586 C.

781-gms: (3.2 moles) of powdered' dicyclohexylcarbamylchloride was added to a -solution containing 350 gms. (3.3 moles) of ,dimethylaminm ethylthiol (preparedas described in Example 1) dissolved in 2000 ml. ofpyridine: :The mixture was stirred and heated under reflux at a temperature of 100-105C; for'a'period of 3 hours, and the mixturewas then cooled to, room temperature.

- was evaporated inqvacuo at a temperaturebelow 50 C. until a mush resulted, This residual material-was treated in: the -manner-describecl in Example 3 to producex948- gms. of dimethylaminoethylthioldicyclohexylurethane; M. P.:'48- 50" (2.; yield approximately of theory.

} Example 7 (7 948 -gms of dimethylaminQethylthioldicyclo- The nearly-solid mass was dissolved in 1000 ml. ofwaterandth aqueous solution- 9 hexylurethane, prepared as described in Example 6, wasreacted with. ethyl iodide, according to the procedure described in Example 4, to produce 1465 gms. of dimethylethyl-Bthiolethyl ammonium iodide dicyclohexylurethane; M. P. 190-191 0.; yield approximately 98% of theory. Analysis-Calcd for C19H37ON2SI.1/2H2O; C, 47.79; H, 8.02; N, 5.87.. Found: C, 47.90; H, 7.78; N, 5.63.

Example 8 2715- gms. of dimethylethyl-;3-thiolethyl ammonium' iodide dicyclohexylurethane, prepared as described in Example 7, was reacted with silver sulfate according to the procedure described in Example5 to produce 2188 gms. of dimethylethyl-,Q-thiolethyl ammonium sulfate dicyclohexylurethane; M. P. 143-144" C.; yield approximately 97% of theory. Analysis.Calcd for C3aH'z406N4S355 H2O; C, 51.96; H, 9.75; N, 6.37; HzO,11.27. Found: C, 51.73; H, 9.60; N, 6.41; E20, 11.17.

' Example 9 31 gms. of dimethylaminoethylthioldicyclohexylurethane, prepared as described in Example 6, was reacted with 85 gms. of n-propyl iodide, utilizing substantially the same procedure as that described in Example 4 for reacting dimethylaminoethylthioldibutylurethane with ethyl iodide, to produce 20 gms. of dimethyl-n-propyl-pthiolethyl ammonium iodide dicyclohexylurethane; M. P. 149-151 C.; yield approximately 41.7% of theory. Analysis.'-C'alcd for Cz oHaeONzSI Example 11 31 gms. of dimethylaminoethylthioldicyclohexylurethane, prepared as described .in Example 6, was reacted with 92 gms. of n-butyliodide, utilizing substantially the same procedure described in Example 4, to produce 28.5 gms. of dimethyl-n-butyl-p-ethio1ethyl ammonium iodide dicyclohexylurethane; M. P. 16l.5-162.5 C.; yield approximately 57.5% of theory. Analysis- Calcd for C21I-I41ON2SI; C, 50.80; H, 8.32; N, 5.64. Found: C, 51.10; H, 8.15; N, 5.63.

Example 12 28.5 gms. of dimethyl-n-butyl-pthiolethyl ammonium iodide dicyclohexylurethane was reacted with silver sulfate, according to the procedure described in Example 5, to produce 23.7 gms. of dimethyl-n-butyl-p-thiolethyl ammonium sulfate dicyclohexylurethane; M. P. 99-99.5 0.; yield approximately 87% of theory. Analysis.-Calcd for C42He20cN4Sc.6I-I20; C, 53.47; H, 10.04; N, 5.94; H2O, 11.45; Found: C, 53.47; H, 9.90; N, 5.94; H2O, 11.12.

Example 13 31 gms. of dimethylaminoethylthioldicyclohexylurethane, prepared as described in Example 6, was reacted with n-amyl iodide, utilizing the substantially same procedure as that described in Example 4, to produce 36 gms. of dimethyl-namyl-fi-thiolethyl .a'mmonium hexylurethane; M. P. 179-180 0.; yield approximately 71% of theory. Ana1ysis.--Calcd for C22H43ON2SI; C, 51.75; H, 8.49; N, 5.48. Found: C, 51.96; H, 8.38; N, 5.64.

Example 14 36 gms. of dimethyl-n-amyl-p-thiolethyl ammonium iodide dicyclohexylurethane, prepared as described in Example 13, was reacted with silver sulfate, utilizing substantially the same procedure as that described in Example 5, to produce 294 gms. of dimethyl-n-amyl-p-thiolethyl ammonium sulfate dicyclohexylurethane; M. P.

99 105 C.; yield approximately 92% of theory. Analysis.-Calcd for C44H8cOsN4Sa3H20; N, 6.10; E20, 5.88.. Found: N, 6.03; H20, 5.50.

Example 15 31 gms. (0.1 mole) of dimethylaminoethylthioldicyclohexylurethane, prepared as described in Example 6, was dissolved in 200 ml. of diethyl ether, 31 gms. (0.2 mole) of diethyl sulfate was added, and the mixture was allowed to stand at room temperature overnight. The crystals that formed were recovered by filtration, washed with ether and dried in vacuo to produce 29 gm. of dim'ethylethylp-thiolethyl ammonium ethyl sulfate dicyclohexylurethane; M. P. 178-179 0.; yield approximately 62.4% of theory. Analysis.-

Calcd for C21H-12O5N2S2; C, 54.04; H, 9.07; N,

6.00. Found: C, 53.88; H, 8.87; N, 5.93.

Example 16 n-Diamylamine was reacted with phosgene in the presence of xylene, utilizing substantially the same procedure described for reacting n-dibutylamine with phosgene in Example 2, and the residual material obtained after evaporation of the xylene was fractionally distilled in vacuo using a Vigreux column to produce diamylcarbamylchloride; B. P. 112 114 C./1 mm.

62.6 gms. of diamylcarbamylchloride, preparedas described on the preceding page, was reacted with 33 gms'. of dimethylaminoethylthiol, prepared as described in Example 1, and the reaction product was treated in substantially the same manner as described in Example 6, to produce 75.6 gms. of dimethylaminoethylthioldiamylurethane, which was obtained as a liquid; yield approximately 94% of theory.

Example 17 60.6 gms. of dimethylaminoethylthioldiamylurethane, prepared as described in Example 16, was reacted with ethyl iodide, utilizing substantially the same procedure as that described in Example 4, to produce gms. of dimethylethyl-fithiolethyl ammonium iodide diamylurethane which was obtained as an amorphous mass; yield approximately 97% of theory. Analysis. Calcd for C17H37ON2SI; C, 45.94; H, 8.39; N, 6.30. Found: C, 45.89; H, 8.02; N, 6.38.

Ezcample 18 90 gms. of dimethylethyl-fi-thiolethyl ammonium iodide diamylurethane, prepared as described in Example 17, was reacted with silver sulfate, utilizing substantially the same procedure as that described in Example 5, to produce 69 gins. of dimethylethyl-p-thiolethyl ammonium sulfate diamylurethane; M. P. 124-125 C.;

iodide dicyclo- 11 yield approximately 91% of theory. Analysiss-e Calcd1 for C34H74O6N4S3.1.5H2O; H2O, 3.56. Found; ,HzO, 3.85. Sample dried to constant. weightat 80 C./1 mm. Analysis.Calcd for C34H7406N4S3; N, 7 .67 .Found: N, 8.18;v

Example 19 attached to; the'nitrogen:atom"of thecarbaniyli 15 grnapf dimethylaminoethylthioldiarnylurethane, prepared as describedgin Example 16, was dissolved in 100 ml. of diethyl ether, 15.4 gms. of diethyl sulfate was added to the solution and the resulting mixture was .allowed to stand overnight. No crystallization took.p1ace.. The mixture .was then heated under reflux for an additional 2 1 hours, without any formation of crystals- Theu'ethereal mixture was extracted with two 25 m1. portions of. water, the combined aqueous bamyl' chloride to produce; the corresponding ;d1.

extracts. were washed with ether and the other. I

layersyvere discarded- .IIhepH of the aqueous solution was adjusted. 17016.4 by the additionof 10% aqueous barium. hydroxide solution, asmallv amount of activated charcoal was added, and the mixture was filtered. The traces of barium thioldicyclohexylurethane.

ion werememoved-from the filtrate by adding aminute'amount of ammonium sulfate and a slight-turbidity was removed by 7 adding activated charcoal-and filtering. The solution was evapo rated-in-vacuo to-a syrup and the syrup was airdriedto constant weight? During the drying period;the syrup crystallized slowly, and the crystalline masses were broken up during the drying periode I'here was-thus obtained 12 gms.- of dimethylethyl;3-thiolethylammonium ethyl sulfate" diamylurethane-;-M.- P. 55-56 0.; yield approximately 55% of theoryr- Ana1ysis.Calcd for C19H42O5N2Sa H2O; 0.50.51; H, 9.59; N, 6.19;- E20, 1.99. Found: C, 5Q .2Q; 1- I, 9.08; H, 6.36; 120,185.

Modifications maybe made incarrying out the present invention without departing from the spirit and scope thereof. Insofar as these changesand modifications are within the purwherein R1 and R2 are saturated hydrocarbon..-.

grouping to. produce a .thioluretha'n'e of the formulaz. i

wherein R1 and R2 are saturated hydrocarbon radicals.

2. The process which "comprises reacting dimethylamino -ethylthiolwith; a dialkyl. carbam chloride to produce the correspondingt-dimethyls aminoethylthiol-dialkylurethane;

3. The process; Which-1 comprises reacting dimethylamino-ethylthiol :with axdicycloalkyl .ca

methylaminoethylthioldicycloalkylurethana.

4. The process'which comprises reacting dimethylamino-ethylthiol: with clicyclohex-yl, -car bamyl chloride to produce dimethylaminoethylr,

5. Thiolurethanes havingythe formula R: on;

radicals.

6. Dimethylaminoethylthiol-dialkylurethanesm '7. Dimethylaminoethylthiol dicycloalkylure-a; V thanes.

View of the annexed claims-they are to be considered'part-ofour invention.

We claim: 1. The process which comprisesreactingdimethylamino-ethylthiol wit-hacarbamyl chloride having-twp saturated hydrocarbon substituents' 8. Dimethylaminoethylthiol. -..dicyclohexyluree thane.

JOHNJ'W'EIJLARD.

Septl' 30; 1948'. .ii 

1. THE PROCESS WHICH COMPRISES REACTING DIMETHLAMINO-ETHYLTHIOL WITH A CARBAMYL CHLORIDE HAVING TWO SATURATED HYDROCARBON SUBSTITUENTS ATTACHED TO THE NITROGEN ATOM OF THE CARBAMYL GROUPLING TO PRODUCE A THIOLURETHANE OF THE FORMULA: 